This invention relates to compounds useful for the treatment of diseases affected by disorders of the serotonin-affected neurological systems, such as depression and anxiety. More specifically, the present invention is directed to aryl piperazinyl cyclohexyl derivatives useful for the treatment of such disorders.
Pharmaceuticals which enhance the neurotransmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological means which caused them to possess numerous undesired side-effects. The more recently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism cannot fully account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors which suppress the firing activity of 5-HT neurons, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients. (See, e.g., Le Poul et al., Arch. Pharmacol., 352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5HT1A antagonists would potentially increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al., Trends Neurosci., 19:378-383 (1996), suggest a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
European Patent Application No. 0714894A1 discloses the preparation of the following compounds as 5HT1A agonists for the treatment of migraine headaches. 
wherein:
Axe2x80x94B is xe2x80x94CHxe2x80x94CH, or xe2x80x94Cxe2x95x90CHxe2x80x94;
X is H, halo, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl, benzyloxy, hydroxy or carbaxamido;
Y is O, S or a bond;
n is 1-4; and
Ar is 1-naphthyl, 2-naphthyl, phenyl or phenyl, mono-substituted with a substituent selected from the group consisting of halo, C1-4 alkoxy, C1-4 alkylthio, C1-4 benzyloxy hydroxy or trifluoromethyl.
U.S. Pat. No. 5,627,196 discloses compounds of the following formula as having effects on serotonin-related systems. 
wherein
r is 0-4;
s is 0-1; and
D is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl, irnidazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl group;
X is hydrogen, phenyl, hydroxy or methoxy provided that X is hydrogen or phenyl
where r is 0; and
R is xe2x80x94NHxe2x80x94R1, 
Malleron et al., J. Med. Chem. 36:1194-1202 (1983)) discloses indole derivatives as serotonin uptake inhibitors having the basic formula: 
wherein A may be: 
The compounds of this invention are aryloxy piperidinyl indoles represented by Formula I: 
wherein:
R1 and R2 form a carbocyclic ring of 5 to 7 carbon atoms, wherein said ring may be saturated or unsaturated and may contain one or more heroatoms; and
X is independently hydrogen, cyano, carbamoyl, halogen or alkoxy; or pharmaceutically acceptable salts thereof.
The compounds of the present invention are preferably those of Formla I, wherein:
R1 and R2 form a carbocyclic ring of 5-6 carbon atoms, containing one or more heteroatoms; and X is hydrogen; or pharmaceutically acceptable salts thereof.
Most preferably, the compounds of the present invention are selected from the following:
3-{1-[2-(2,3-Dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-1H-pyrrolo[2,3-b]pyridine;
3-{1-[2-(1H-Indol-4-yloxy)-ethyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-1H-pyrrolo[2,3-b]pyridine; and
5-{2-[4-(1H-Pyrrolo[2,3-b]-pyridine-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethoxy}-quinoline.
As used herein, the term xe2x80x9calkoxyxe2x80x9d is meant to include both straight and branched carbon chains containing 1-6 carbon atoms. The term xe2x80x9chalogenxe2x80x9d is meant to include fluorine, chlorine, bromine and iodine. The term xe2x80x9cheteroatomxe2x80x9d is meant to include oxygen, nitrogen and sulfur.
The compounds of Formula I also may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known to the art are formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfaric, phosphoric and nitric acids.
The compounds of the present invention may be prepared by any suitable method which will be recognized by those skilled in the art. However, the present compounds may be advantageously prepared according to Scheme 1 set forth below. 
Specific exemplification of the production of representative compounds of this invention is provided in the following procedures.
7-azindole (10 g, 85 mmol), 4-piperidone (34 g, 0.22 mol) and potassium hydroxide (16.83 g, 0.3 mol) were heated to reflux in 150 ml methanol overnight. The reaction was cooled, filtered and concentrated to give an orange slurry. The slurry was then extracted with methylene chloride and washed with water. The organic layer was dried over anhydrous magnesium, filtered and concentrated to afford 14.2 g (84%) of product as a solid: mp 195-199xc2x0 C.
Pyrogallol (5 g, 0.04 mol) was dissolved in 2-butanone (600 ml) to which potassium carbonate (1.82 g, 0.013 mol) was added. The mixture was stirred at reflux while 1,2-dibromoethane (2.48 g, 1.14 ml, 0.013 mol) was slowly added dropwise. The reaction was allowed to stir overnight and then cooled to room temperature. The mixture was poured into water (100 ml) and extracted with methylene chloride (200 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum. Chromatography (5% methanol-methylene chloride) afforded 2.74 g (45%) of product as a clear oil. MS EI m/e 152 (M+)
To solution of 5-hydroxybenzodioxane (1.0 g, 6.5 mmol) and 2-chloroethanol (0.79 g, 9.9 mmol), triphenylphosphine (2.6 g, 9.9 mmol) in tetrahydrofuran (50 ml) was slowly added diisopropylazidodicarbimide (DIAD) (2.0 g, 9.8 mmol). After 2 hours, another 1.5 eq of triphenylphosphine, DIAD, and 2-chloroethanol was added and the reaction stirred for another 2 hours. The reaction mixture was poured into water (100 ml), and extracted with methylene chloride (100 ml). The organic layer was separated and dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. Chromatography (20% ethyl acetate-hexanes) afforded 1.7 g (76%) of product as a white solid: mp 70.5-72.5xc2x0 C.
Elemental analysis for C10H11ClO3 
Cal""d: C, 55.96; H, 5.17
Found: C, 55.57; H, 5.20
To a solution of 4-hydroxyindole (4 g, 30 mmol), 2-chloroethanol (4.83 g, 60 mmol), triphenylphosphine (15.7 g, 60 mmol) in anhydrous tetrahydroufuran (40 ml) was slowly added diisopropyl azodicarboxylate (12.1 g, 60 mmol). The reaction was allowed to stir for 2.5 hours at room temperature, then poured into methylene chloride (250 ml), washed with water (3xc3x97100 ml) and dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (20% hexanes-ethyl acetate) to remove triphenylphosphine (20% methylene chloride-hexanes) afforded 2.94 g (50%) of product as a white solid: mp 69.5-72xc2x0 C.
A 100 ml three-neck oven dry flask was cooled under nitrogen. 5-Hydroxy quinoline (2 g, 14 mmol) was added as well as triphenylphosphine (5.42 g, 21 mmol) suspended in 50 ml anhydrous tetrahydrofuran. 2-Chloroethanol (1.3 ml, 21 mmol) was slowly added to above reaction mixture via syringe, followed by adding DEAD (2.98 ml, 21 mmol) via syringe. A second 1.5 eq of 2-chloroethanol, triphenylphosphine and DEAD was added. The reaction mixture was poured into 100 ml water and extracted by methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. Chromatographed (20% ethyl acetate-hexanes) afforded 2.31 g (82%) of product as a solid: mp 75-78xc2x0 C.